Aligned forces: Origins and mechanisms of cancer dissemination guided by extracellular matrix architecture

Organized extracellular matrix (ECM), in the form of aligned architectures, is a critical mediator of directed cancer cell migration by contact guidance, leading to metastasis in solid tumors. Current models suggest anisotropic force generation through the engagement of key adhesion and cytoskeletal complexes drives contact-guided migration. Likewise, disrupting the balance between cell–cell and cell–ECM forces, driven by ECM engagement for cells at the tumor–stromal interface, initiates and drives local invasion. Furthermore, processes such as traction forces exerted by cancer and stromal cells, spontaneous reorientation of matrix-producing fibroblasts, and direct binding of ECM modifying proteins lead to the emergence of collagen alignment in tumors. Thus, as we obtain a deeper understanding of the origins of ECM alignment and the mechanisms by which it is maintained to direct invasion, we are poised to use the new paradigm of stroma-targeted therapies to disrupt this vital axis of disease progression in solid tumors.